RTKs, such as EGFR, HER2, MET and RET, are often inappropriately active (due to mutation or overexpression) in a wide array of epithelial malignancies. My laboratory cloned two of the three members of the mammalian Cbl protein family and demonstrated that they are negative regulators of the EGFR in mammalian cells. We have shown that Cbl proteins are RING finger E3s and that all mammalian Cbl proteins mediate ubiquitination of the activated EGFR, resulting in the degradation of the activated EGFR signaling complex. Work in my lab, in collaborations with other laboratories, and by other investigators has shown the Cbl proteins regulate many RTKs and signaling pathways. In addition, my lab has contributed to the structure function analysis of the Cbl proteins. More recently my laboratory has identified and characterized proteins which interact with and modify the function of Cblc, the least well characterized Cbl protein, identified and are characterizing E2 proteins that interact with the Cbl proteins, and identified mutant forms of Cbl proteins in human and mouse epithelial tumors. Ongoing work: 1) investigates the spectrum of ubiquitin conjugating enzymes (E2s) that function with Cbl protiens. 2) investigates the proteins that collaborate with Cbl proteins to mediate RTK downregulation by identifying proteins in the active complex by mass spec analysis. 3) studies mutations of Cbl proteins found in murine and human solid tumors. 4) develop a screen to identify Cblb E3 inhibitors